Oral clefts, which include cleft lip (CL), cleft lip and palate (CLP) and cleft palate (CP), and collectively represent one of the most common birth defects in humans. Oral clefts have a complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Candidate gene studies and genome wide linkage studies have yielded compelling but inconsistent evidence that multiple genes control risk to oral clefts, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrients. We have assembled a consortium of experienced investigators who have accumulated a very large collection of DNA samples on cases and their families (mostly case-parent trios) that are now available for genome wide studies, which represents the next level of genetic investigation for oral clefts. Specific aims are: 1. To conduct a genome wide analysis on 2000 case-parent trios ascertained through a case with isolated, non-syndromic oral cleft (CL, CLP or CP) and their parents using high throughput genotyping of single nucleotide polymorphic (SNP) markers to test for linkage and LD. The initial analysis will consist of individual tests for gene effects, with appropriately haplotype analysis and novel mapping approaches for larger chromosomal regions that allows for heterogeneity among populations. 2. To test for interaction between genes and common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (collected by interview) which have been implicated as environmental risk factors for oral clefts. Availability of serum biomarker measures of nutritional status from one component populations (Utah) allows important further tests for GxE interactions. 3. To test for interaction between genes that may explain some of the conflicting results in the literature with regard to genes controlling risk to oral clefts. This proposal offers a unique opportunity to expand and extend the search for genes controlling risk to oral clefts, creates the opportunity for quick replication across populations and will direct further molecular studies of genes controlling normal craniofacial development. [unreadable] [unreadable] [unreadable]